Clinical Relevance of Minimal Residual Viremia during Long-Term Therapy with Nucleos(t)ide Analogues in Patients with Chronic Hepatitis B.

Abstract

Successful therapy of chronic hepatitis B with nucleos(t)ide analogues (NUCs) has been defined by undetectable HBV-DNA determined with conventional PCR (lower limit of detection (LLD) 60-80 IU/mL) in clinical registration trials. However, current EASL guidelines recommend highly sensitive real-time PCR (LLD<10-20 IU/mL) and define treatment response by HBV-DNA<10 IU/mL. We evaluated frequency and relevance of minimal residual viremia (MRV) during long-term NUC-treatment in a real-life setting. Frozen serum samples (HBV-DNA negative by in-house PCR, LLD <73 IU/mL) were re-analyzed by real-time PCR (LLD<10 IU/mL, Abbott, Germany). MRV was defined by real time PCR positivity and conventional PCR negativity. 237 samples of six HBsAg carriers and 27 NUC-treated CHB patients were analyzed (treatment period 28 (11-111) months, different treatment regimens with mono- or combination therapy). MRV was detected in 31/33 individuals (n = 160/237 serum samples) and more frequent in HBsAg carriers (95%) and HBeAg positive (87%) compared to HBeAg negative patients (53%) (p<0.0001, respectively). Five HBsAg carriers, five HBeAg positive, and four HBeAg negative individuals were continuously HBV-DNA positive. MRV was not significantly more often observed during NUC-monotherapies compared to combination therapies. Concomitant immunosuppressive therapy was present in nine cases and did not influence the results. Viral resistance occurred in three immunocompetent patients with adefovir or lamivudine monotherapy. MRV is frequently observed during long-term NUC-therapy. Adjustment of treatment with highly potent NUCs does not seem to be necessary in case of minimal residual viremia in a real-life setting.